(+/-)-Terodiline: an M1-selective muscarinic receptor antagonist. In vivo effects at muscarinic receptors mediating urinary bladder contraction, mydriasis and salivary secretion

The affinity and selectivity of racemic terodiline (N-tert-butyl-1-methyl-3,3-diphenylpropylamine HCl) for muscarinic receptor subtypes was determined from functional responses of rabbit vas deferens (M1), guinea pig atria (M2) and bladder detrusor muscle (M3). (+/-)-Terodiline was found to be about as potent as pirenzepine in the rabbit vas deferens (Kb = 15 and 31 nM, respectively) and at least as selective for M1 relative to M2 (11-fold) and M3 (19-fold) receptors. Like pirenzepine, (+/-)-terodiline does not distinguish between M2 and M3 receptors in vitro. The peripheral actions of (+/-)-terodiline were evaluated in vivo in terms of its ability to induce mydriasis, and to inhibit salivary secretion and urinary bladder contraction. (+/-)-Terodiline given s.c. was equipotent in inhibiting intravesical bladder pressure and carbachol-induced salivary secretion (ID50 = 24 and 35 mg/kg, respectively), and in increasing pupil diameter (ED50 = 59 mg/kg). These results suggest that the in vivo actions of racemic terodiline at (M3) receptors mediating bladder contraction may not be separable from its actions at receptors mediating mydriasis and salivation. Moreover, its effects on the pupil and salivary glands are apparently not mediated through M1 receptors. Together, these findings help clarify the action of (+/-)-terodiline in the treatment of neurogenic bladder.